Prostate cancer is the most commonly occurring non-skin cancer in men and is estimated to account for 27% of all cancers diagnosed in men in the United States in 2014. The androgen receptor (AR) signaling pathway is found to be highly active in both early- and late-stage prostate cancer. Androgen ablation therapy, which is commonly used to treat advanced prostate cancer, is often effective in causing initial tumor regression. However, patients who progress on androgen ablation therapy develop a more aggressive androgen-independent cancer phenotype known as castration-resistant prostate cancer. The AR signaling pathway retains activity in patients with castration-resistant prostate cancer in spite of the low levels of circulating androgens. Mechanisms that contribute to the retention of AR activity under castrate conditions include AR gene amplification, mutations that render the AR responsive to other steroids and growth factors, crosstalk with survival pathways such as AKT and MAPK, intra-tumoral and adrenal steroidogenesis, and the expression of constitutively active AR splice variants.
Second generation anti-androgens that target the ligand-binding domain (LBD) of the AR have been developed for castration-resistant prostate cancer treatment. Enzalutamide (MDV3100) is currently approved for the treatment of patients with metastatic castration-resistant prostate cancer. ARN-509, a structural analogue of enzalutamide, is currently under Phase III clinical development. In vitro and in vivo studies show that both MDV3100 and ARN-509 inhibit ligand-binding to the AR. Additionally, both agents decrease the transcriptional activity, target gene expression, nuclear localization, and DNA binding of the AR. MDV3100 and ARN-509 are effective in preventing the growth of androgen-dependent VCaP cells in vitro and in decreasing tumor growth in castrate mice in vivo. In a Phase III clinical trial in patients that had progressed on chemotherapy, MDV3100 increased overall survival by approximately five months compared to placebo. A clinical study showed that MDV3100 decreased the risk of radiographic progression and death in chemotherapy naïve men.
Although clinical data indicate the benefits of MDV3100 therapy, evidence indicates the emergence of resistance in castration-resistant prostate cancer (CRPC) cell lines and clinical samples that have undergone prolonged treatment with second generation anti-androgens, MDV3100 and ARN-509. MDV3100 is ineffective in preventing the growth of CRPC cell lines like 22Rv1 unless the AR splice variant, AR-V7, is specifically knocked-down. The appearance of a specific missense mutation (F876L) has been demonstrated in the AR LBD in cell lines, xenograft tumors, and clinical samples that have undergone prolonged treatment with MDV3100 and ARN-509. The appearance of this mutation is accompanied by rising prostate-specific antigen (PSA) levels, indicating resistance to anti-androgen therapy. Additionally, patients who are poor responders to MDV3100 treatment show increased expression of the glucocorticoid receptor (GR) in bone marrow biopsies. Elevated GR expression has been implicated as a compensatory mechanism to overcome AR antagonism in vitro and in vivo. Therefore, the benefits of anti-androgen therapy are short-lived.